Whitening Agent And Skin External Preparation

ABSTRACT

The present invention provides a compound having an excellent inhibitory action on melanin production and being useful as a whitening agent, and a skin external preparation containing the compound. The whitening agent of the present invention comprises, as an active ingredient, a compound represented by formula (1) or a pharmacologically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein, R 1 , R 3 , R 4 , and R 6  are each independently C 1-3  alkyl; and R 2  and R 5  are each independently a hydrogen atom or C 1-3  alkyl.

RELATED APPLICATIONS

This application claims the priority of Japanese Patent Application No.2008-29106 filed on Feb. 8, 2008 and Japanese Patent Application No.2008-199606 filed on Aug. 1, 2008, which are incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates to a whitening agent and a skin externalpreparation, and particularly, to an active ingredient thereof.

BACKGROUND OF THE INVENTION

Pigmentation in the skin such as pigmented spots and freckles areresulted from hyperpigmentation of melanin in the epidermis. Thehyperpigmentation is caused by acceleration of melanin production inepidermal melanocytes triggered by hormone abnormality or UVstimulation.

A whitening agent has been mixed into a skin external preparation withan aim to prevent and improve such abnormal melanin pigmentation. Atpresent, as ingredients that are mixed into a skin external preparationas a whitening agent, there are vitamin C derivative, kojic acid,arbutin (4-hydroxyphenyl-β-D-glucopyranoside), Rucinol(4-n-butylresorcinol), ellagic acid, etc, which are known to have aninhibitory action on melanin production.

However, a whitening agent fully satisfactory in terms of the effect,safety, and the like has not yet been obtained, and thereforedevelopment of a new whitening agent has been demanded.

On the other hand, Patent Literature 1 describes a pyrazole pyrimidinecompound having a regulatory action on a potassium channel.

Also, Patent Literatures 2 to 4 describe a pyrazole pyrimidine compoundhaving a pest control activity on rice blast disease, leaf blightdisease of rice and sesame, cucumber powdery mildew, and the like.

Further, Patent Literature 5 describes a pyrazole-pyrimidine compounduseful as an analgesic.

However, these literatures are totally silent on an inhibitory action onmelanin production and a whitening effect.

-   -   Patent Literature 1: WO2006/100212    -   Patent Literature 2: Japanese Unexamined Patent Publication No.        S54-117029    -   Patent Literature 3: Japanese Unexamined Patent Publication No.        S54-147921    -   Patent Literature 4: Japanese Unexamined Patent Publication No.        562-404    -   Patent Literature 5: Japanese Examined Patent Publication No.        S42-19593

DISCLOSURE OF THE INVENTION Problem to be Solved by the Invention

The present invention has been accomplished in view of theaforementioned problem of the conventional art. An object of the presentinvention is to provide a compound having an excellent inhibitory actionon melanin production and being useful as a whitening agent, and a skinexternal preparation containing the compound.

Means To Solve The Problem

The present inventors conducted thorough research to solve theaforementioned problem. As a result, they have found that a specificpyrimidylpyrazole compound has an excellent inhibitory action on melaninproduction and also has extremely low cytotoxicity, thereby completingthe present invention.

That is, the whitening agent of the present invention comprises, as anactive ingredient, a pyrimidylpyrazole compound represented by thefollowing formula (I) or a pharmacologically acceptable salt thereof:

wherein, R₁, R₃, R₄, and R₆ are each independently C₁₋₃ alkyl; and R₂and R₅ are each independently a hydrogen atom or C₁₋₃ alkyl.

The present invention also provides the whitening agent, wherein R₂ andR₅ are hydrogen atoms.

The present invention also provides the whitening agent, wherein R₁, R₃,R₄, and

R₆ are methyl.

The present invention also provides the whitening agent, wherein theactive ingredient inhibits melanin production.

The present invention also provides a skin external preparation and acosmetic comprising any of the aforementioned pyrimidylpyrazolecompounds or a pharmacologically acceptable salt thereof.

EFFECT OF THE INVENTION

The whitening agent of, the present invention has an excellentinhibitory action on melanin production and also has extremely lowcytotoxicity; therefore, it can be suitably mixed into a skin externalpreparation as a whitening agent.

BEST MODE FOR CARRYING OUT THE INVENTION

The whitening agent of the present invention is represented by thefollowing formula (1):

In the formula (I), R₁, R₃, R₄, and R₆ are each independently C₁₋₃alkyl.

In the present invention, the “C₁₋₃ alkyl” is a linear, branched, orcyclic saturated hydrocarbon group having from 1 to 3 carbon atoms.Examples thereof include a methyl group, an ethyl group, an n-propylgroup, an isopropyl group, and a cyclopropyl group. Preferred alkylincludes methyl and ethyl, and particularly preferred alkyl is methyl.

R₂ and R₅ are each independently a hydrogen atom or C₁₋₃ alkyl.

An example of the preferred compound as an active ingredient of thewhitening agent of the present invention is the compounds wherein R₁,R₃, R₄, and R₆ are methyl.

Another example of the preferred compound as an active ingredient of thewhitening agent of the present invention is the compounds wherein R₂ andR₅ are hydrogen atoms.

The compound of the formula (I) can be synthesized by a known method orcommercially available. Hereinbelow, representative synthesis examplesare described; however, the present invention is not limited thereto.When the molecule has a functional group which blocks or might block areaction, an appropriate protecting group is preferably used to allowthe reaction to proceed efficiently. The use of the protecting group canbe carried out according to, for example, Protective Groups in OrganicSynthesis by Theodora W. Greene and Peter G. M. Wuts.

Further, when an isomer such as a conformational isomer, a geometricisomer, and an optical isomer is present, a pure isomer or geometricisomer can be obtained by appropriately selecting a raw material and areaction condition and performing a separation operation. In the presentinvention, a pure isomer of the compound of the formula (I) as well as amixture thereof are also included.

A compound of the formula (1) can be obtained by a reaction shown in thefollowing scheme 1.

In scheme 1, a reaction of a hydrazine compound (2) with a1,3-dicarbonyl compound (3a) or a 1-sulfonyl-3-carbonyl compound (3b)can be carried out, for example, in an appropriate solvent such asmethanol in the presence of an acid catalyst such as hydrochloric acidor acetic acid, while heating as needed. This reaction can be carriedout according to, for example, a method described in Japanese UnexaminedPatent Publication No. S62-404 (Patent Literature 4), Tetrahedron Lett.,45, 4265 (2004), Gazzetta Chemica Italiana, 93, 100 (1963), or the like.

The hydrazine compound (2) to be used as a starting material in thescheme 1 can be commercially available or synthesized by a known method.

For example, by a reaction shown in the following scheme 2 using anamine compound (3) as a starting material, the objective hydrazinecompound (2) can be obtained. This reaction can be carried out accordingto a method described in Japanese Unexamined Patent Publication No.H8-208620.

Alternatively, by a reaction shown in the following scheme 3, theobjective hydrazine compound (2) can be obtained from a pyrimidinecompound (4) having a leaving group Z (for example, a halogen). Thisreaction can be carried out according to, for example, a methoddescribed in Chem. Pharm. Bull., 17(7), 1467 (1969), Chem. Pharm. Bull.,11 (11), 1382 (1963), Yakugaku Zasshi, 73, 635 (1953), or the like.

Other compounds used in the aforementioned reactions can be synthesizedby appropriately combining known methods.

The compound of the formula (I) can be converted into an acid-additionsalt by an ordinary method as needed. Examples of acid in theacid-addition salt include an inorganic salt such as hydrochloric acid,hydrobromic acid, sulfuric acid, and phosphoric acid, and an organicacid such as acetic acid, propionic acid, citric acid, lactic acid,oxalic acid, maleic acid, fumaric acid, succinic acid, tartaric acid,and methanesulfonic acid.

The compound of the formula (I) has an excellent inhibitory action onmelanin production while exhibiting extremely low cytotoxicity.Therefore, the present compound is useful as a whitening agent and canbe suitably mixed into various skin external preparations, particularlya skin external preparation intended to improve or prevent pigmentedspots, freckles, skin dullness, and the like.

When the compound of the formula (I) is mixed into the skin externalpreparation as the whitening agent, the compound amount is, in the totalamount of the external agent, typically 0.0002% by mass or more,preferably 0.002% by mass or more. When it is too low, the effect cannotbe fully exerted. Although no limitation is imposed on the upper limit,it is typically 30% by mass or less, preferably 20% by mass or less, andmore preferably 5% by mass or less. When the compound is excessivelymixed in, not only a remarkable effect reasonably expected from theincreased amount may not be obtained but also formulation designing andusability may be affected.

Other than adding the compound of the formula (I), the skin externalpreparation of the present invention can be produced by an ordinarymethod.

In addition to the compound of the formula (I), other ingredientsnormally used in a skin external preparation such as a cosmetic productand a pharmaceutical product can be appropriately added to the skinexternal preparation of the present invention as needed as far as theeffect of the present invention is not adversely affected. Examples ofsuch an ingredient include oil, a humectant, an ultraviolet protectiveagent, an antioxidant, a metal ion chelating agent, a surfactant, apreservative, a moisturizer, a fragrance, water, an alcohol, athickener, powder, a colorant, a crude drug, and various kinds ofmedicinal ingredients.

Further, other whitening agents such as vitamin C, magnesium ascorbylphosphate, ascorbyl glucoside, arbutin, kojic acid, Rucinol, ellagicacid, tranexamic acid, and linoleic acid can be appropriately added.

The skin external preparation of the present invention is widelyapplicable to the fields of cosmetics, drugs, and quasi drugs. Noparticular limitation is imposed on the form of the skin externalpreparation as long as it is applicable to the skin. Any form such as asolution, an emulsion, a solid, a semi-solid, a powder, a powderdispersion, a water-oil-separated two-phase liquid, awater-oil-powder-separated three-phase liquid, an ointment, a gel, anaerosol, a mousse, and a stick can be applied. Further, the skinexternal preparation can be provided in any use form including a facialcosmetic such as a lotion, an emulsion, a cream, a pack, an essence, anda gel, and a makeup cosmetic such as a foundation, a makeup base, and aconcealer.

Hereinbelow, the present invention will be further described withspecific examples. However, the present invention is not limitedthereto.

EXAMPLES

A test for melanin production inhibition by the compounds of the formula(1) was conducted. The test method is as follows.

Melanin Production Inhibition Test

(1) Inoculation of Cells and Addition of Test Substances

Mouse B16 melanoma cells were inoculated in a six well plate at 100,000cells/well. The next day, test substance solutions (solvent: DMSO) wereadded.

(2) Cell Proliferation Test

Three days after the addition of the test substance solution, the mediumwas removed by aspiration. Then 1 ml of EMEM medium containing 10%Alamar Blue solution was added, and a reaction was allowed to proceed at37° C. After 30 minutes, 100 μL of the reaction mixture was: transferredto a 96 well plate and fluorescence was measured at an excitationwavelength of 544 nm and a measurement wavelength of 590 nm. Using thevalue thus measured as a relative value of cell count, a ratio of thecell count (% cell count) of the test substance-added group to the testsubstance-absent group (group in which only the solvent was added) wascalculated. The higher the % cell count, the lower the cytotoxicity. Itwas determined that a compound having the % cell count of 80% or morewas non-cytotoxic, and that a compound having the % cell count of lessthan 80% was cytotoxic.

(3) Quantification of Melanin

The cells after the cell proliferation test were washed with PBS threetimes, and then lysed by addition of 200 μL of 1M NaOH to measure anabsorbance at 475 nm. Using the value thus measured as a relative valueof the melanin amount, a ratio of the melanin amount (%) of the testsubstance-added group to the test substance-absent group (group in whichonly the solvent was added) was calculated. The lower the ratio of themelanin amount, the higher the melanin production-inhibitory effect. Inthe final concentrations of the test substances at which the compoundwas determined to be non-cytotoxic, the minimum final concentration ofthe test substance at which the ratio of the melanin amount (%) was 80%or less was provided as a minimum concentration for inhibition ofmelanin production (ppm). The inhibitory effect on melanin productionwas evaluated according to the following criteria.

⊚: the minimum concentration for inhibition of melanin production was 1ppm or less.

◯: the minimum concentration for inhibition of melanin production wasmore than 1 ppm and 10 ppm or less. x: no inhibitory effect on melaninproduction was exhibited at 10 ppm or less

-   -   (the ratio of the melanin amount was not 80% or less even at 10        ppm or less).

The results of melanin production inhibition test using the compounds ofthe present invention are shown in Table 1.

Any of the compounds shown in Table 1 was acknowledged to have aninhibitory effect on melanin production, and most of them exhibited theeffect at such an extremely low concentration as 1 ppm or less.

TABLE 1 Inhibitory effect on No. R₁ R₂ R₃ R₄ R₅ R₆ melanin production 1Me H Me Me H Me ⊚  2# Me H Me Me H Me ⊚ 3 Me H Me Et H Et ⊚ 4 Me H Me MeMe Me ⊚ 5 Me Me Me Me H Me ⊚ #HCI salt, Me: methyl, Et: ethyl

The minimum concentrations at which an inhibitory effect on melaninproduction was significantly exhibited in melanoma B16 cells werecompared between the heterocyclic compounds of the present invention andarbutin, which is actually used in clinical practice within a range of0.1 to 30% by mass in a composition. As representative examples, resultsof compounds 1, 3, and 4 are shown.

TABLE 2 Test compound Minimum concentration (%) Arbutin 5 × 10⁻⁴Compound 1 1 × 10⁻⁶ Compound 3 3 × 10⁻⁶ Compound 4 3 × 10⁻⁶

As shown in Table 2 above, the compounds of the present inventionexhibited an inhibitory effect on melanin production in melanoma B16cells at a concentration of approximately 1/170 to 1/500 of arbutin.Thus, it is understood that the compounds of the present inventionexhibit the effect at a very low concentration compared to arbutin.

Hereinbelow, representative synthesis examples of the heterocycliccompounds used for the whitening agent of the present invention will beshown. Various heterocyclic compounds can be obtained by carrying out areaction according to the below-described synthesis examples using acorresponding raw material.

Synthesis Example 1 Synthesis of Pyrimidylpyrazole Compounds

In a 100 mL recovery flask, hydrazine compound (Raw material A, 9.25mmol), 1,3-dicarbonyl compound (Raw material B, 9.25 mmol),ion-exchanged water (3.0 mL) and acetic acid (3.0 mL) were added andrefluxed for one hour. Upon completion of the reaction, a 10% aqueoussolution of sodium hydroxide was added to the reaction mixture to adjustthe pH to 10 or higher. The mixture was extracted with ethyl acetate,and the organic phase was washed with saturated brine once and driedover anhydrous magnesium sulfate. The solvent was distilled off underreduced pressure, and the residue was purified by silica gel columnchromatography (hexane:ethyl acetate=10:1) to give each of thepyrimidylpyrazole compounds shown in Table 3.

TABLE 3 No. Structure Raw material A Raw material B NMR Yield 1

(4,6-Dimethylpyrimidin- 2-yl)hydrazine Acetylacetone ¹H-NMR (CDCl₃):2.34(3H, s), 2.53(6H, s), 2.64(3H, s), 6.01(1H, s), 6.88(1H, s) 58% 3

(4,6-Dimethylpyrimidin- 2-yl)hydrazine 3,5-Heptanedione ¹H-NMR (CDCl₃):1.22- 1.30(6H, m), 2.53(6H, s), 2.75(2H, q), 3.13(2H, q), 6.10(1H, s),6.88(1H, s) 79% 4

(4,6-Dimethylpyrimidin- 2-yl)hydrazine 3-Methyl-2,4- pentanedione ¹H-NMR(CDCl₃): 1.97(3H, s), 2.29(3H, s), 2.52(6H, s), 2.65(3H, s), 6.85(1H, s)39%

Synthesis Example 2 Synthesis of2-(3,5-dimethylpyrazol-1-yl)-4,6-dimethyl pyrimidine hydrochloride(Compound 2)

In a 50 mL recovery flask,2-(3,5-dimethylpyrazol-1-yl)-4,6-dimethylpyrimidine (compound 1) (1.00g, 4.94 mmol) and methanol (4.94 mL) were added. LON hydrochloric acid(4.94 mL) was added to the mixture dropwise at room temperature and thenstirred for an hour at room temperature. Upon completion of thereaction, the solvent was distilled off under reduced pressure, and theresulting solid was recrystallized from a mixed solvent of ethanol andethyl acetate to give 0.93 g of2-(3,5-dimethylpyrazol-1-yl)-4,6-dimethylpyrimidine hydrochloride(Compound 2) (yield 79%).

¹H-NMR (DMSO-d₆): 2.21 (3H, s), 2.47(6H, s), 2.55 (3H, s), 6.15 (1H, s),7.15 (1H, s), 7.20 (1H, s).

Synthesis Example 3 Synthesis of2-(3,5-dimethylpyrazol-1-yl)-4,5,6-trimethylpyrimidine (Compound 5)

In a 100 mL recovery flask, 1-amidino-3,5-dimethylpyrazole nitrate (1.00g, 4.97 mmol), 3-methyl-2,4-pentandione (0.60 g, 5.22 mmol), potassiumcarbonate (1.37 g, 9.94 mmol), and methanol (6.63 mL) were added. Themixture was stirred for 30 minutes at room temperature, and thenrefluxed for 6 hours. Upon completion of the reaction, the solid wasremoved by filtration, and the residue was extracted with ethyl acetateonce. The organic phase was washed with saturated brine once and driedover anhydrous magnesium sulfate. The solvent was distilled off underreduced pressure, and the residue was purified by silica gel columnchromatography (chloroform:hexane=1:1, and then chloroform) to give 0.10g of 2-(3,5-dimethylpyrazol-1-yl)-4,5,6-trimethylpyrimidine (compound 5)(yield 9%).

¹H-NMR (DMSO-d₆): 2.18 (3H, s), 2.22 (3H, s), 2.46 (6H, s), 2.49 (3H,s), 6.06 (1H, s).

Hereinbelow, Formulation Examples of the skin external preparation ofthe present invention are shown. In each Formulation Example, one ormore compounds of the present invention can be used. Any of the skinexternal preparations shown in Formulation Examples below exerts awhitening effect because of the by the addition of the compound of thepresent invention.

Formulation Example 1 Cream Formulation

Stearic acid 5.0% by mass Stearyl alcohol 4.0 Isopropyl myristate 18.0Glyceryl monostearate 3.0 Propylene glycol 10.0 Compound of the presentinvention 0.1 Caustic potash 0.2 Sodium bisulfate 0.05 Preservative q.s.Fragrance q.s. Ion-exchanged water balance

(Production Method)

Propylene glycol and caustic potash were dissolved in ion-exchangedwater, and the resulting mixture was heated to and maintained at 70° C.(aqueous phase). Other components were mixed and melted by heat, andmaintained at 70° C. (oil phase). The oil phase was gradually added tothe aqueous phase, and after the complication of the addition, theresulting mixture was maintained at 70° C. for some time to allow areaction to proceed. Subsequently, the mixture was homogeneouslyemulsified by a homomixer, and cooled to 30° C. while thoroughlystirring.

Formulation Example 2 Cream Formulation

Stearic acid 5.0 by mass % Sorbitan monostearate 2.5 Polyoxyethylene(20) sorbitan monostearate 1.5 Arbutin 7.0 Sodium bisulfate 0.03Propylene glycol 10.0 Compound of the present invention 0.05 Glyceryltrioctanoate 10.0 Squalene 5.0 Octyl p-dimethylaminobenzoate 3.0Disodium ethylenediaminetetraaceiate 0.01 Ethylparaben 0.3 Fragranceq.s. Ion-exchanged water balance

(Production Method)

Propylene glycol and disodium ethylenediaminetetraacetate were dissolvedin ion-exchanged water and the resulting mixture was maintained at 70°C. (aqueous phase). Other components were mixed and melted by heat, andmaintained at 70° C. (oil phase). The oil phase was gradually added tothe aqueous phase. The mixture was preliminarily emulsified at 70° C.,homogeneously emulsified by a homomixer, and then cooled to 30° C. whilethoroughly stirring.

Formulation Example 3 Cream Formulation

Solid paraffin 5.0% by mass Beeswax 10.0 Petrolatum 15.0 Liquid paraffin41.0 Glyceryl monostearate 2.0 POE (20) sorbitan monolaurate 2.0 Soappowder 0.1 Borax 0.2 Compound of the present invention 0.05 Sodiumbisulfite 0.03 Ethylparaben 0.3 Fragrance q.s. Ion-exchanged waterbalance

Production Method

Powder soap and borax were added to ion-exchanged water and dissolvedwith heat, and the resulting mixture was maintained at 70° C. (aqueousphase). Other components were mixed and melted by heat, and maintainedat 70° C. (oil phase). While stirring, the oil phase was gradually addedto the aqueous phase to allow a reaction to proceed. Upon completion ofthe reaction, the mixture was homogeneously emulsified by a homomixer,and then cooled to 30° C. while thoroughly stirring.

Formulation Example 4 Milky Lotion Formulation

Stearic acid 2.5% by mass Cetyl alcohol 1.5 Petrolatum 5.0 Liquidparaffin 10.0 POE (10) monooleate 2.0 Polyethylene glycol 1500 3.0Triethanolamine 1.0 Carboxyvinyl polymer 0.05 Compound of the presentinvention 0.01 Sodium bisulfite 0.01 Ethylparaben 0.3 Fragrance q.s.Ion-exchanged water balance

(Production Method)

Carboxyvinyl polymer was dissolved in a small amount of ion-exchangedwater (phase A). Polyethylene glycol 1500 and triethanolamine were addedto the remaining ion-exchanged water and dissolved with heat, and theresulting mixture was maintained at 70° C. (aqueous phase). Othercomponents were mixed and melted by heat, and maintained at 70° C. (oilphase). The oil phase was added to the aqueous phase and preliminarilyemulsified. After addition of phase A, the resulting mixture washomogeneously emulsified by a homomixer and then cooled to 30° C. whilethoroughly stirring.

Formulation Example 5 Milky Lotion Formulation

Microcrystalline wax 1.0% by mass Beeswax 2.0 Lanolin 20.0 Liquidparaffin 10.0 Squalane 5.0 Sorbitan sesquioleate 4.0 POE (20) sorbitanmonooleate 1.0 Propylene glycol 7.0 Compound of the present invention1.0 Sodium bisulfite 0.01 Ethylparaben 0.3 Fragrance q.s. Ion-exchangedwater balance

(Production Method)

Propylene glycol was added to ion-exchanged water, and the resultingmixture was heated and maintained at 70° C. (aqueous phase). Othercomponents were mixed and melted by heat, and maintained at 70° C. (oilphase). While stirring the oil phase, the aqueous phase was graduallyadded to the oil phase. The resulting mixture was homogeneouslyemulsified by a homomixer and then cooled to 30° C. while thoroughlystirring.

Formulation Example 6 Jelly Formulation

95% Ethanol 10.0% by mass Dipropylene glycol 15.0 POE (50) oleyl ether2.0 Carboxyvinyl polymer 1.0 Caustic soda 0.15 L-arginine 0.1 Compoundof the present invention 5.0 Sodium 2-hydroxy-4-methoxybenzophenonesulfonate 0.05 Trisodium ethylenediaminetetraacetate dihydrate 0.05Methylparaben 0.2 Fragrance q.s. Ion-exchanged water balance

(Production Method)

Carboxyvinyl polymer was homogeneously dissolved in ion-exchanged water.Separately, the compound of the present invention and POE (50) oleylether were dissolved in 95% ethanol and then added to the aqueous phase.After addition of the remaining components, the resulting mixture wasneutralized by caustic soda and L-arginine to increase the viscosity.

Formulation Example 7 Essence Formulation

(Phase A) Ethyl alcohol (95%) 10.0% by mass POE (20) octyldodecanol 1.0Pantothenyl ethyl ether 0.1 Compound of the present invention 2.0Methylparaben 0.15 (Phase B) Potassium hydroxide 0.1 (Phase C) Glycerol5.0 Dipropylene glycol 10.0 Sodium bisulfite 0.03 Carboxyvinyl polymer0.2 Purified water balance

(Production Method)

Each of Phase A and Phase C was homogeneously dissolved, and Phase A wasadded to Phase C to be solubilized. After addition of Phase B, theresulting mixture was packed in a container.

Formulation Example 8 Pack Formulation

(Phase A) Dipropylene glycol 5.0% by mass POE (60) hydrogenated castoroil 5.0 (Phase B) Compound of the present invention 0.05 Olive oil 5.0Tocopherol acetate 0.2 Ethylparaben 0.2 Fragrance 0.2 (Phase C) Sodiumbisulfite 0.03 Polyvinyl alcohol (saponification degree of 13.0 90 andpolymerization degree of 2,000) Ethanol 7.0 Purified water balance

(Production method)

Each of Phase A, Phase B, and Phase C was homogeneously dissolved, andPhase B was added to Phase A to be solubilized. After addition of PhaseC, the resulting mixture was packed in a container.

Formulation Example 9 Solid Foundation Formulation

Talc 43.1% by mass Kaolin 15.0 Sericite 10.0 Zinc oxide 7.0 Titaniumdioxide 3.8 Yellow iron oxide 2.9 Black iron oxide 0.2 Squalane 8.0Isostearic acid 4.0 POE sorbitan monooleate 3.0 Isocetyl octanoate 2.0Compound of the present invention 0.5 Preservative q.s. Fragrance q.s.

(Production Method)

Powdery components from talc to black iron oxide shown above werethoroughly mixed by a blender. To this mixture were added oilycomponents from squalane to isocetyl octanoate shown above, the compoundof the present invention, preservative, and fragrance. The resultingmixture was thoroughly kneaded, packed in a container, and then formed.

Formulation Example 1.0 Emulsion Foundation (Cream-Type) Formulation

(Powder part) Titanium dioxide 10.3% by mass Sericite 5.4 Kaolin 3.0Yellow iron oxide 0.8 Red iron oxide 0.3 Black iron oxide 0.2 (Oilphase) Decamethylcyclopentasiloxane 11.5 Liquid paraffin 4.5Polyoxyethylene-modified dimethylpolysiloxane 4.0 Compound of thepresent invention 0.5 (Aqueous phase) Purified water 50.0 1,3-Butyleneglycol 4.5 Sorbitan sesquioleate 3.0 Preservative q.s. Fragrance q.s.

(Production Method)

The aqueous phase was stirred with heat and then the powder part, whichhad been fully mixed and pulverized, was added. The mixture was treatedwith a homomixer and then the oil phase, which had been mixed with heat,was added. The mixture was treated with a homomixer and then fragrancewas added while stirring. The mixture thus obtained was cooled to roomtemperature.

Formulation Example 11 Lotion

(1) Compound of the present invention 0.05% by mass (2) Aspartic acid1.0 (3) Tocopherol acetate 0.01 (4) Glycerol 4.0 (5) 1,3-Butylene glycol4.0 (6) Ethanol 8.0 (7) POE (60) hydrogenated castor oil 0.5 (8)Methylparaben 0.2 (9) Citric acid 0.05 (10) Sodium citrate 0.1 (11)Fragrance 0.05 (12) Purified water balance

(Production Method)

(2), (4), (5), (9), and (10) were dissolved in (12) to provide apurified water solution. Separately, (1), (3), (7), (8), and (11) weredissolved in (6), and the resulting mixture was added to theaforementioned the purified water solution to be solubilized. Themixture thus obtained was filtrated to provide a lotion.

Formulation Example 12 Lotion

A: Alcohol phase Ethanol 5.0% by mass POE oleyl ether 2.02-Ethylhexyl-p-dimethylaminobenzoate 0.18 Compound of the presentinvention 0.1 Fragrance 0.05 B: Aqueous phase 1,3-Butylene glycol 9.52-O-Ethyl ascorbic acid 0.5 Sodium pyrrolidonecarboxylate 0.5 Wheyextract 5.0 Nicotinamide 0.3 Glycerol 5.0 Hydroxypropyl-β-cyclodextrin1.0 Trisodium hydroxyethylethylenediamine triacetate 1.0 Lysine 0.05Tranexamic acid 1.0 Purified water balance

(Production Method)

Alcohol phase A was added to Aqueous phase B and solubilized to providea lotion,

Formulation Example 13 Cream (Whitening)

Trans-4-(trans-aminomethylcyclohexanecarbonyl) 1.0% by massaminomethylcyclohexanecarboxylic acid hydrochloride Potassium4-methoxysalicylate 1.0 3-O-Ethylascorbic acid 1.0 Linoleic acid 0.3Sodium lipoate 1.0 Compound of the present invention 3.0 CoenzymeQ10(CoQ10) 0.03 Petrolatum 2.0 Dimethylpolysiloxane 2.0 Ethanol 5.0Behenyl alcohol 0.5 Batyl alcohol 0.2 Glycerol 7.0 1,3-Butylene glycol5.0 Polyethylene glycol 20000 0.5 Jojoba oil 3.0 Squalane 2.0Phytosteryl hydroxystearate 0.5 Pentaerythritol tetra(2-ethylhexanoate)1.0 Polyoxyethylene hydrogenated castor oil 1.0 Potassium hydroxide 0.1Sodium pyrosulfite 0.01 Sodium hexametaphosphate 0.05 Stearylglycyrrhetinate 0.1 Pantothenyl ethyl ether 0.1 Arbutin 7.0 Tranexamicacid 2.0 Tocopherol acetate 0.1 Sodium hyaluronate 0.05p-Hydroxybenzoate ester q.s. Trisodium edetate 0.054-t-Butyl-4′-methoxydibenzoylmethane 0.1 Glyceryl diparamethoxycinnamate0.1 mono-2-ethylhexanoate Yellow iron oxide q.s. Xanthan gum 0.1Carboxyvinyl polymer 0.2 Purified water balance

Formulation Example 14 Two-Phase Cream (Sunscreen)

Tranexamic acid 2.0% by mass Potassium 4-methoxysalicylate 1.0 Compoundof the present invention 0.03 Dimethylpolysiloxane 5.0Decamethylcyclopentasiloxane 25.0 Trimethylsiloxysilicate 5.0Polyoxyethylene/methylpolysiloxane copolymer 2.0 Dipropylene glycol 5.0Dextrin palmitate-coated fine-particle zinc oxide (60 nm) 15.0Dipotassium glycyrrhizinate 0.02 Glutathione 1.0 Thiotaurine 0.05Sophora flavescens extract 1.0 Paraben q.s. Phenoxyethanol q.s.Trisodium edetate q.s. 2-Ethylhexyl p-methoxycinnamate 7.5Dimethyldistearylammonium hectorite 0.5 Spherical poly(alkyl acrylate)powder 5.0 Butylethylpropanediol 0.5 Purified water balance Fragranceq.s.

Formulation Example 15 Gel (Whitening)

Potassium 4-methoxysalicylate 0.1% by mass Rucinol 0.3 Dihydrolipoicacid 1.0 Lamium album var. barbatum 0.1 Dimethylpolysiloxane 5.0Glycerol 2.0 1,3-Butylene glycol 5.0 Polyethylene glycol 1500 3.0Polyethylene glycol 20000 3.0 Cetyl octanoate 3.0 Citric acid 0.01Sodium citrate 0.1 Sodium hexametaphosphate 0.1 Compound of the presentinvention 1.0 Dipotassium glycyrrhizinate 0.1 Ascorbyl glucoside 2.0Tocopherol acetate 0.1 Scutellaria baicalensis extract 0.1 Saxifragastolonifera extract 0.1 Trisodium edetate 0.1 Xanthan gum 0.3 Acrylicacid/alkyl methacrylate 0.05 copolymer (Pemulen TR-2) Agar powder 1.5Phenoxyethanol q.s. Dibutylhydroxytoluene q.s. Purified water balance

Formulation Example 16 Pack (Moisturizing)

Trans-4-aminomethylcyclohexanecarboxylic acid 10.0% by mass methylamidehydrochloride Dihydrolipoamide 1.0 Rosa multiflora fruit extract 0.1Ethanol 10.0 1,3-Butylene glycol 6.0 Polyethylene glycol 4000 2.0 Oliveoil 1.0 Macadamia nut oil 1.0 Phytosteryl hydroxystearate 0.05 Lacticacid 0.05 Sodium lactate 0.1 Disodium L-ascorbyl sulfate 0.1 Compound ofthe present invention 0.5 Potassium 2-L-Ascorbyl α-tocopheryl phosphate0.1 Vitamin E acetate 0.1 Fish collagen 0.1 Sodium chondroitin sulfate0.1 Sodium carboxymethyl cellulose 0.2 Polyvinyl alcohol 12.0p-Hydroxybenzoate q.s. Purified water balance Fragrance q.s.

Formulation Example 17 Lotion (Moisturizing)

Tranexamic acid 1.0% by mass Potassium 4-methoxysalicylate 1.0 Lipoicacid 10.0 Hamamelis 0.1 Silica-coated zinc oxide 0.1 Hypotaurine 0.1Sophora flavescens extract 0.1 Peach kernel extract 0.1 Beech sproutextract 0.1 Retinol 0.1 Compound of the present invention 0.01 Ethylalcohol 5.0 Glycerol 1.0 1,3-Butylene glycol 5.0 Polyoxyethylenepolyoxypropylene decyltetradecyl ether 0.2 Sodium hexametaphosphate 0.03Trimethylglycine 1.0 Sodium polyaspartate 0.1 Potassium 2-L-Ascorbylα-tocopheryl phosphate 0.1 Thiotaurine 0.1 Green tea extract 0.1Peppermint extract 0.1 Iris root extract 1.0 Trisodium EDTA 0.1Carboxyvinyl polymer 0.05 Potassium hydroxide 0.02 Phenoxyethanol q.s.Purified water balance Fragrance q.s.

1-13. (canceled)
 14. A skin external preparation comprising (a) adermatologically acceptable carrier or adjuvant, and (b) as an activeingredient, a pyrimidylpyrazole compound represented by formula (1) or apharmacologically acceptable salt thereof:

wherein, R₁, R₃, R₄, and R₆ are each independently C₁₋₃ alkyl; and R₂and R₅ are each independently a hydrogen atom or C₁₋₃ alkyl.
 15. Theskin external preparation of claim 14, wherein R₂ and R₅ are hydrogenatoms.
 16. The skin external preparation of claim 14, wherein R₁, R₃,R₄, and R₆ are methyl groups.
 17. The skin external preparation of claim14, wherein the active ingredient inhibits melanin production.
 18. Theskin external preparation of claim 14, wherein the preparation is acosmetic.
 19. A method for inhibiting melanin production comprisingtopically applying to the skin of a subject in need thereof apreparation comprising an effective amount of a pyrimidylpyrazolecompound represented by formula (I) or a pharmacologically acceptablesalt thereof:

wherein, R₁, R₃, R₄, and R₆ are each independently C₁₋₃ alkyl; and R₂and R₅ are each independently a hydrogen atom or C₁₋₃ alkyl.
 20. Themethod of claim 19, wherein the pyrimidylpyrazole compound acts as askin-whitening agent.